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RESEARCH FRONT
Contents Vol 68(1)

Probing the Mode of Neurotransmitter Binding to GABA Receptors Using Selectively Fluorinated GABA Analogues

Nathan Absalom A , Izumi Yamamoto A B , David O’Hagan C , Luke Hunter D and Mary Chebib A E
+ Author Affiliations
- Author Affiliations

A Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.

B Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8585, Japan.

C School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK.

D School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.

E Corresponding author. Email: mary.collins@sydney.edu.au




Nathan Absalom was awarded his Ph.D. degree by the University of New South Wales in 2004, where he studied the activation mechanisms of ligand-gated ion channels. He was awarded a Wellcome Trust Training Fellowship to work at the University of Oxford and the MRC Harwell before taking a post-doctoral position researching the pharmacology of ion channels at the University of Sydney in 2009.


Izumi Yamamoto obtained her Ph.D. degree from the University of Sydney in 2012, after which she joined a laboratory at the National Institute for Physiological Sciences in Japan as a post-doctoral researcher. She was awarded a post-doctoral fellowship by the Japan Society for the Promotion of Science (JSPS) in 2013.


David O'Hagan is Professor of Organic Chemistry within the School of Chemistry at the University of St Andrews in Scotland, where he has research interests in organo-fluorine chemistry and fluorine related biochemistry. He studied undergraduate chemistry at the University of Glasgow and did his Ph.D. studies at Southampton University. After a post-doctoral term with Heniz G. Floss at the Ohio State University, he took up his first academic position at the University of Durham in 1986, before moving to St Andrews University in 2000. He is currently Head of the School of Chemistry.


Luke Hunter completed his Ph.D. degree at the University of Sydney in 2004. He undertook post-doctoral research at the University of Melbourne, the University of St Andrews, UNSW Australia, and the University of Sydney before taking up his current appointment at UNSW, where he is presently Senior Lecturer in Chemistry. Luke's interests are in the areas of natural product synthesis, peptidomimetics, and organofluorine chemistry.


Mary Chebib completed her Ph.D. degree at Griffith University in 1994. She undertook post-doctoral research at the Department of Pharmacology, University of Sydney, before taking up her current appointment at the Faculty of Pharmacy, University of Sydney, where she is Professor of Pharmaceutical Neuroscience. Mary's interests are in the areas of medicinal chemistry, neuropharmacology, and ligand-gated ion channels.

Australian Journal of Chemistry 68(1) 23-30 https://doi.org/10.1071/CH14456
Submitted: 18 July 2014  Accepted: 28 August 2014   Published: 20 October 2014

Abstract

Stereoselective fluorination is a useful technique for controlling the conformations of organic molecules. This concept has been exploited to create conformationally biased analogues of the neurotransmitter gamma-aminobutyric acid (GABA). Mono- and di-fluorinated GABA analogues are found to adopt different conformations, due to subtle stereoelectronic effects associated with the C–F bond. These conformationally biased GABA analogues exhibit different shape-dependent selectivity patterns towards GABAA, GABAB, and GABAC receptors, providing valuable information on the binding modes of the natural ligand at these medicinally important targets.


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